Pharmaceutical containers with low adsorption/absorption of active ingredients, and a method of testing materials for adsorption/absorption of active ingredients

ABSTRACT

The present invention relates to a container comprising, one or more polyolefins exhibiting less than 20% sorption of one or more active ingredients as determined by a suitably acceptable method; and a composition comprising one or more active ingredients. The invention also provides a method of determining whether a package material will provide a desired stability of an active ingredient of a pharmaceutical composition; a method of maintaining the concentration of an active ingredient of a pharmaceutical composition upon storage in a container; and a method of manufacturing a storage container utilizing a pharmaceutically acceptable material comprising one or more active ingredients in a therapeutically effective concentration.

FIELD OF THE INVENTION

This application claims the benefit of U.S. Provisional Patent Application No. 60/483,367 filed Jun. 27, 2003. The present invention relates to suitable materials for use in storage-stable containers for aqueous pharmaceutical compositions, such as prostaglandin formulations, and to containers comprising such materials. The present invention also relates to a method for determining if a material is suitable for use in storage-stable containers for aqueous pharmaceutical compositions.

BACKGROUND

Pharmaceutical compositions comprising one or more active ingredients must possess certain levels of stability and purity in order to be suitable for safe and efficacious administration to patients. The pharmaceutical composition may also contain other components, e.g. excipients, such as flavoring agents and preservatives. Such compositions are considered stable if the concentration of active ingredient(s) can be maintained at the level specified on the label for the maximum anticipated shelf-life under given environmental conditions. A pharmaceutical composition is considered unstable when the potency of the active ingredient(s) is lost.

The potency of a drug product may decline over time during storage due to various reasons, such as degradation of the active ingredient(s), reaction of the active ingredient(s) with excipients or container materials, leaching of the active ingredient(s) through the container wall, and absorption/adsorption of the active ingredient(s) into/to the container wall. Similarly, the purity of a medicinal preparation may also change during storage due to leaching of chemicals into the drug preparation from the container materials, from the labels on the containers, or from the environment where the packaged medicinal product is stored. Thus, the containers used for packaging medicinal preparations can significantly affect the stability and purity of the preparations contained therein. Preservatives, for example, may also permeate the container wall and as a result, their preservative value is diminished. The solvent of the composition may also permeate the container wall, which will increase the concentration of the active ingredient and of the other components of the composition.

One example of a group of one or more active ingredients is prostaglandins. Prostaglandins are relatively unstable medical agents and are used for treatment of various conditions, including glaucoma, which is an eye disorder afflicting various mammals, including primates and humans, and is characterized in that it increases intraocular pressure (ocular hypertension). Prostaglandins such as, but not limited to, latanoprost, are susceptible to adsorption/absorption by plastic packaging components, and this adsorption/absorption decreases the potency of the compositions upon storage.

Containers commonly used for medicinal products include glass containers, polypropylene containers, and polyethylene containers. (See e.g. U.S. Pat. No. 6,235,781). However, since glass containers are rigid and not squeezable, they are not very suitable for medicinal preparations which are conveniently dispensed on a drop-by-drop basis. Typical user-friendly containers, dispensers, or bottles for medicinal preparations are formed from e.g. polyethylene, polypropylene, or polyethylene terephthalates (PET), which in most instances provide a suitable combination with a pharmaceutical preparation, resulting in a packaged medicinal product that is user-friendly for dispensing of the pharmaceutical preparation on a drop-by-drop basis.

The ophthalmic products XALATAN® (comprising approximately 50 μg/ml latanoprost) and XALCOM® (comprising approximately 50 μg/ml latanoprost and 5 mg/ml timolol) are packaged in bottles. The bottle is typically made of clear low-density polyethylene with a clear low-density polyethylene dropper tip, a high-density polyethylene screw cap, and a clear low-density polyethylene overcap. Unopened bottles are stored at a recommended temperature of approximately 2-8° C. Upon storage at the recommended temperature, the concentrations of latanoprost and latanoprost/timolol, respectively, are stably maintained in the products.

Plastic containers have some drawbacks since the active agent, depending on the choice of plastic material employed for the container, can be absorbed and/or adsorbed by the container material. This absorption/adsorption decreases the potency of the formulations during the storage. In order to reduce or prevent the absorption and/or adsorption of e.g. certain prostaglandins, the plastic containers comprising the pharmaceutical compositions are commonly kept in refrigerators until opened, and once opened, they can be kept in room temperature and used within a limited period of time, typically 1-2 months. The requirement that the ophthalmic preparation is to be kept refrigerated reduces the availability of the treatment in countries where such storage conditions are less available or reliable. Furthermore, even where available, refrigeration of the preparation increases the cost of the treatment to the patient, and thus, further reduces its availability to those in need.

Despite these advances, there is still an unmet need for a method for storing such preparation over periods of time without refrigeration. There is also a need for a packaged medicinal product and method for packaging pharmaceutical compositions, which can increase the stability of the pharmaceutical composition or prevent the loss of an ingredient of the composition.

Furthermore, there is a need for a rapid and convenient method of testing candidate materials for their absorption/adsorption properties with respect to one or more active ingredients to be contained in vessels made by the material.

SUMMARY OF THE INVENTION

The present invention relates to a container comprising,

-   -   a) one or more polyolefins exhibiting less than 20% sorption of         one or more active ingredients as determined by a suitably         acceptable method; and     -   b) a composition comprising said one or more active ingredients.

In another embodiment of the invention, the container according to the invention, wherein the suitably acceptable method comprises the steps of:

-   -   a) providing a sample of said container having a surface area of         S;     -   b) immersing said sample in a volume V of said composition, such         that the surface area to volume ratio S/V is in the range of         from about 1 to about 100 cm⁻¹; and     -   c) subjecting said sample immersed in said composition to a         temperature T that is above room temperature, for a period of         time P that is less than two weeks.

In another embodiment, the container according to the invention, wherein said P is 10 days.

In yet another embodiment, the container according to the invention, wherein said T is 56° C.

In yet another embodiment, the container according to the invention, wherein said one or more polyolefins comprise either ethylene monomers, propylene monomers, or both.

In yet another embodiment, the container according to the invention, wherein said one or more polyolefins are selected from the group consisting of low-density polyethylene (LDPE), high-density polyethylene (HDPE), polypropylene (PP), and blends thereof.

In yet another embodiment, the container according to the invention, wherein said one or more polyolefins are selected from the group consisting of homopolymers of low-density polyethylene (LDPE), homopolymers of high-density polyethylene (HDPE), and homopolymers of polypropylene(PP).

In another embodiment, the container according to the invention, wherein said one or more polyolefins are selected from the group consisting of DuPont™ 20 LDPE, Chevron 5502 HDPE, Atofina 3020 PP, polypropylene homopolymers, low ethylene content (<8%) polypropylenes, and polymers (HDPE, PP) with low content of additives (<5%) and with low flexural modulus (<200 kpsi).

In another embodiment, the container according to the invention, wherein said one or more polyolefins exhibit less than 10% sorption of one or more said active ingredient(s).

In yet another embodiment, the container according to the invention, wherein said one or more polyolefins exhibit less than 5% sorption of said active ingredient(s).

In yet another embodiment, the container according to the invention, wherein said pharmaceutical composition is an ophthalmic composition.

In yet another embodiment, the container according to the invention, wherein said ophthalmic composition is for treatment of glaucoma.

In yet another embodiment, the container according to the invention, wherein said one or more active ingredient(s) comprises one or more physiologically acceptable derivatives of prostaglandin F (PGF), in which the omega chain has the formula:

the bond between C₁₃ and C₁₄ is optionally a single bond or double bond;

-   D is a chain with 2-3 carbon atoms, optionally comprising at least     one heteroatom selected from the group consisting of O, S, and N,     and optionally substituted by one or more substituents selected from     the group consisting of H, C₁-C₅ alkyl, halo, keto and hydroxy; -   R is a     -   (i) phenyl group optionally substituted by one or more         substituents selected from the group consisting of C₁-C₅ alkyl,         C₁-C₄ alkoxy, trifluoromethyl, C₁-C₃ aliphatic acylamino, nitro,         halo, and phenyl; or     -   (ii) an aromatic heterocyclic group having 5-6 ring atoms,         selected from the group consisting of thiozol, imidazole,         pyrrolidine, thiophene and oxazole, optionally substituted by         one or more substituents selected from the group consisting of         C₁-C₅ alkyl, C₁-C₄ alkoxy, trifluoromethyl, C₁-C₃ aliphatic         acylamino, nitro, halo, and phenyl; or     -   (iii) C₃-C₇ cycloalkyl or C₃-C₇ cycloalkylene optionally         substituted by C₁-C₅ alkyl.

In yet another embodiment, the container according to the invention, wherein the concentration of said active ingredient in said composition is in the range of from 0.001% to 5% (w/v).

In another embodiment, a medicinal product comprising a container according to the invention, wherein said container contains a pharmaceutical composition according to the invention.

According to another aspect of the invention, there is provided a method of determining whether a package material will provide a desired stability of an active ingredient of a pharmaceutical composition, said pharmaceutical composition comprising said active ingredient in a therapeutically effective concentration and optionally a pharmaceutically acceptable excipient, dissolved and/or dispersed in an aqueous medium, comprising the steps of:

-   -   (i) providing a sample having a surface area S of said package         material;     -   (ii) immersing said sample of step (i) in a volume V of said         composition, such that the surface area to volume ratio S/V is         in the range of from about 1 to about 100 cm⁻¹;     -   (iii) subjecting said sample immersed in said composition of         step (ii) to a temperature T that is above room temperature, for         a period of time P that is less than two weeks;     -   (iv) following said period of time P of step (iii), calculating         the concentration of said active ingredient; and     -   (v) calculating the stability provided by the sample by         comparing the concentration determined in step (iv) with the         initial concentration of said active ingredient.

In another embodiment, the method according to the invention, said active ingredient(s) are selected from the group consisting of physiologically acceptable derivatives of PGF, in which the omega chain has the formula:

the bond between C₁₃ and C₁₄ is optionally a single bond or double bond;

-   D is a chain with 2-3 carbon atoms, optionally comprising at least     one heteroatom selected from the group consisting of O, S, and N,     and optionally substituted by one or more substituents selected from     the group consisting of H, C₁-C₅ alkyl, halo, keto and hydroxy; -   R is a     -   (i) phenyl group optionally substituted by one or more         substituents selected from the group consisting of C₁-C₅ alkyl,         C₁-C₄ alkoxy, trifluoromethyl, C₁-C₃ aliphatic acylamino, nitro,         halo, and phenyl; or     -   (ii) an aromatic heterocyclic group having 5-6 ring atoms,         selected from the group consisting of thiozol, imidazole,         pyrrolidine, thiophene and oxazole, optionally substituted by         one or more substituents selected from the group consisting of         C₁-C₅ alkyl, C₁-C₄ alkoxy, trifluoromethyl, C₁-C₃ aliphatic         acylamino, nitro, halo, and phenyl; or     -   (iii) C₃-C₇ cycloalkyl or C₃-C₇ cycloalkylene optionally         substituted by C₁-C₅ alkyl.

In yet another embodiment, the method according to the invention, wherein the initial concentration of said one or more active ingredient in said composition is in the range of from 0.001% to 5% (w/v).

In yet another embodiment, the method according to the invention, wherein said surface area to volume ratio S/V is in the range of from about 10 to about 40 cm⁻¹.

In another embodiment, the method according to the invention, wherein said surface area to volume ratio S/V is about 20 cm⁻¹.

In yet another embodiment, the method according to the invention, wherein said temperature T is in the range of from 25° C. to 80° C.

In yet another embodiment, the method according to the invention, wherein said temperature T is in the range of from 50° C. to 60° C.

In another embodiment, the method according to the invention, wherein said period of time P is in the range of from 1 to 10 days.

In yet another embodiment, the method according to the invention, wherein said material comprises one or more polyolefins.

In another embodiment, the method according to the invention, wherein said sample of said material is provided in the shape of discs and/or pellets and/or beads.

According to another aspect of the invention, there is provided a method of maintaining the concentration of an active ingredient of a pharmaceutical composition upon storage in a container, comprising the steps of:

-   -   (i) providing said pharmaceutical composition, comprising said         active ingredient in a therapeutically effective concentration         and optionally a pharmaceutically acceptable excipient,         dissolved and/or dispersed in an aqueous medium;     -   (ii) providing said container, which is comprised, at least         partially, of a pharmaceutically acceptable material comprising         one or more polyolefins, said material exhibiting less than 20%         sorption of said active ingredient as measured by immersing a         sample of said material having a surface area S in a volume V of         said composition, the surface area to volume ratio S/V being         about 20 cm⁻¹, at a temperature of 56° C. for 10 days; and     -   (iii) storing said pharmaceutical composition in said container.

In yet another embodiment, the container and method according to the invention, wherein said active ingredient is latanoprost.

In another embodiment, the container and method according to the invention, wherein said one or more active ingredient(s) is selected from the group consisting of prostaglandin, analogues, and derivatives thereof.

In another embodiment, the container and method according to the invention, wherein said physiologically acceptable derivatives of PGF are selected from the group consisting of 17-phenyl-18,19,20-trinor derivatives, 13,14-dihydro-17-phenyl-18,19,20-trinor derivatives, 16-phenoxy-17,18,19,20-tetranor derivatives, and 16-phenyl-17,18,19,20-tetranor derivatives.

According to another aspect of the invention, there is provided a method of manufacturing a storage container utilizing a pharmaceutically acceptable material comprising one or more active ingredients in a therapeutically effective concentration and optionally a pharmaceutically acceptable excipient, dissolved and/or dispersed in an aqueous medium, wherein said material

-   -   (i) comprises one or more polyolefins; and     -   (ii) exhibits less than 20% sorption of said active         ingredient(s) as measured by immersing a sample of such material         having a surface area S in a volume V of said composition, the         surface area to volume ratio S/V being about 20 cm⁻¹, at a         temperature of 56° C. for 10 days.

Most preferably, the prostaglandin derivatives are 17-phenyl-18,19,20-trinor derivatives, 13,14-dihydro-17-phenyl-18,19,20-trinor derivatives, 16-phenoxy-17,18,19,20-tetranor derivatives, or 16-phenyl-17,18,19,20-tetranor derivatives. The “nor” derivative denotes (a) elimination of one methylene group from a chain, the highest permissible locant being used, or (b) contraction of a ring by one CH₂ unit, the locant being the capital letter identifying the ring. Elimination of two or more methylene groups may be denoted by the prefixes “dinor-”, “trinor-”, “tetranor-” and so on.

Derivatives of these prostaglandins include all pharmaceutically acceptable salts, esters (alkyl esters, such as isopropyl esters) and amides (lower alkyl amides, such as N-diethyl amide) that may be attached to the 1-carboxyl group or any of the hydroxyl groups of the prostaglandin by use of the corresponding alcohol or organic acid reagent, as appropriate. It should be understood that the terms “analogues” and “derivatives” include compounds that exhibit functional and physical responses similar to those of prostaglandins per se.

Specific examples of prostaglandins that are useful in the present invention include the following compounds:

-   1. 17-phenyl-18,19,20-trinor-PGF_(2a)-isopropyl ester; -   2. 15-(R)-17-phenyl-18,19,20-trinor-PGF_(2a)-isopropyl ester; -   3. 16-phenyl-17,18,19,20-tetranor-PGF_(2a)-isopropyl ester; -   4. 20-pentanor-13-prostynoic acid; -   5. latanoprost; -   6. cloprostenol isopropyl ester; -   7. (5Z)-(9S, 11R,     15S)-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic     acid isopropyl ester; -   8. (5Z, 13E)-(9S, 11R,     15R)-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoic     acid amide; -   9. PGF₂, isopropyl ester; -   10. fluprostenol isopropyl ester; -   11. isopropyl [2R(1E, 3R),     3S(4Z),4R]-7-[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroxy-3-furanyl]-4-heptenoate; -   12. 15-keto latanoprost; -   13. bimatoprost; -   14. unoprostone isopropyl; -   15. 15-deoxy-15-fluro-16-phenoxy-17,18,19,20-tetranor-PGF_(2a)     isopropyl ester; -   16.     15-deoxy-15-fluro-16-(3-chlorophenoxy)-17,18,19,20-tetranor-PGF_(2a)     isopropyl ester; -   17.     15-deoxy-15-fluro-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-PGF_(2a)     isopropyl ester; -   18. 15-deoxy-15-difluro-16-phenoxy-17,18,19,20-tetranor-PGF_(2a)     isopropyl ester; -   19.     15-deoxy-15-difluro-16-(3-chlorophenoxy)-17,18,19,20-tetranor-PGF_(2a)     isopropyl ester; -   20.     15-deoxy-15-difluro-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-PGF_(2a)     iso-propyl ester; -   21. 15-deoxy-15-difluro-16-phenoxy-17,18,19,20-tetranor-PGF_(2a)     isopropyl ester; and -   22. DE-085.

According to one aspect of the present invention, there is provided a medicinal product comprising a container according to the invention, which container contains a pharmaceutical composition according to the invention.

The term “package material”, as used herein, means any material that is suitable for containers for pharmaceutical compositions. Such pharmaceutically acceptable materials include, but are not limited to materials comprising one or more polyolefins. Examples of suitable package materials for containers for pharmaceutical compositions include materials comprising ethylene or propylene monomers, or both.

The term “stability provided by a sample or active ingredient”, or the term “stability of an active ingredient” as used herein, refers to the degree of sorption, including absorption and/or adsorption, the material exhibits with respect to a substance exposed to the material. In particular, the term relates to the degree of sorption of an active ingredient of a pharmaceutical composition exhibited by a material. The term “sorption”, as used herein, refers to absorption or adsorption or a combination of absorption or adsorption. The acceptable degree of sorption depends on the active ingredient, the type of material, and recommended storage conditions, such as temperature and storage time, for the pharmaceutical composition in question. For practical and economical purposes, however, it is desirable that the material exhibits less than 20% sorption of said active ingredient(s) in said test. Under certain circumstances, it may be desirable that the material exhibits less than 10% sorption, such as less than 5% sorption, or even lower sorption, of said active ingredient(s) in said test.

The term “pharmaceutical composition”, as used herein, means a composition comprising at least one active ingredient, suitable for use in treatment of humans and animals. A particular type of pharmaceutical composition that is useful according to the invention is an ophthalmic composition. The ophthalmic composition according to the invention may be useful for treatment of glaucoma and/or other ophthalmic conditions.

The term “active ingredient(s)”, as used herein, comprises the therapeutically active compound(s) that provides a desired effect upon administration of a therapeutically effective amount thereof to a human or an animal in need thereof. The active ingredient is commonly provided in a suitable pharmaceutical composition.

The terms “therapeutically effective concentration” and “therapeutically effective amount”, as used herein, means an amount, or a concentration that upon administration of the proper volume results in such an amount, which upon administration thereof to a human or an animal in need thereof exerts desirable therapeutic effects.

As used herein, the term “prostaglandin” or “PG” shall refer to prostaglandins and derivatives and analogues thereof, including pharmaceutically acceptable salts and esters, except as otherwise indicated by context. Prostaglandins may be classified according to their 5-membered ring structure, using a letter designation. Prostaglandins may be further classified based on the number of unsaturated bonds on the side chain. The prostaglandins that may be utilized in the present invention include all pharmaceutically acceptable prostaglandins, their derivatives and analogues, and their pharmaceutically acceptable esters and salts. Such prostaglandins include the natural compounds PGE₁, PGE₂, PGE₃, PGF_(1a), PGF_(2a), PGF_(3a), PGD₂, and PGI₂ (prostacyclin), as well as analogues and derivatives of these compounds which have similar biological activities.

The term “pharmaceutically acceptable excipient”, as used herein, refers to any suitable excipient known in the art. The active ingredient may be associated with an excipient that enhances chemical and physical stability, or provides preservation against microbial contamination or product acceptability, such as taste, smell, tolerability, etc.

In accordance with convention used in the art, the symbol

is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure of the prostaglandin molecule.

By the term “pharmaceutical composition storage container” is herein meant a container suitable for a specified storage. According to a specific aspect of the invention, the container is filled with a pharmaceutical composition as specified herein. The container containing the pharmaceutical composition constitutes a packaged medicinal product. In particular, certain containers contain a pharmaceutical composition comprising prostaglandins, as described in more detail in the following. These medicinal products are especially suitable for ophthalmic use.

DETAILED DESCRIPTION OF THE INVENTION

There is obviously a need for rapid and reliable identification of materials that are suitable for use in containers for storage of pharmaceutical compositions comprising one or more active ingredients over periods of time without refrigeration. There is also a need for a container for storage of pharmaceutical compositions and for a method of packaging pharmaceutical compositions, which can increase the stability of active ingredient contained in the pharmaceutical composition or prevent the loss of an active ingredient of the composition.

The invention is based on the insight that it is possible to establish a criterion for selecting packaging materials that will provide an improved stability of the active ingredient. The criterion is based on monitoring of sorptive losses of the active ingredient to candidate materials under accelerated conditions by using a fixed ratio of candidate material surface area to composition volume. Using this criterion, it is now possible to establish significant differences between materials that would otherwise be considered to be equivalent in all respects.

From this insight, we have now established an inventive method, which makes it possible to determine if a material comprising one or more polyolefins is suitable for being used as packaging containers for aqueous compositions comprising one or more active ingredients, such as certain prostaglandins, i.e. if the container will be a storage-stable container for aqueous compositions comprising such one or more active ingredients. The method is based on a rapid screening technique, which comprises monitoring absorptive and/or adsorptive losses of prostaglandins to a candidate material under accelerated conditions, including incubation above room temperature. Furthermore, we have also found that by using this method, certain brands of low-density polyethylene (LDPE) and high-density polyethylene (HDPE) are capable of providing improved storage stability to compositions comprising prostaglandins, i.e. the prostaglandins will substantially not be adsorbed and/or absorbed by the polymeric material.

The sample of the material that is to be tested as package material is conveniently provided in the shape of discs and/or pellets and/or beads. The surface area S of the sample is defined as the entire area that can be exposed to the pharmaceutical composition. Without being limited thereto, it is preferred that the sample surface area S is in the range of 1 cm²-10 000 cm², such as in the range of 1 cm²-1000 cm². In a typical experimental setup, the sample surface area S is approximately 40 cm².

The material sample is contacted with a volume V of the pharmaceutical composition. This can be achieved in various ways, e.g. by dipping the sample in the composition or by adding the composition to the sample. Without being limited thereto, it is preferred that the volume V of the pharmaceutical composition is in the range of 1 mL-100 mL, such as in the range of 1 mL-10 mL. In a typical experimental setup, the volume V of the pharmaceutical composition is approximately 2 mL.

In general, the surface area to volume ratio S/V may vary in a rather wide range in the method according to the invention. The S/V ratio should be optimized to obtain meaningful and relevant information with regard to the acceptability of a packaging material to be formed into a suitable container for a specific active ingredient. It is important to choose S and V such that all the material to be tested is covered by the fluid. For practical purposes, however, it is preferable that the ratio S/V is in the range of from about 1 to about 100 cm⁻¹. In specific embodiments of the method according to the invention, the ratio S/V is in the range of from about 10 to about 40 cm⁻¹, such as about 20 cm⁻¹.

Following the immersion, i.e. the contacting of the material sample with the pharmaceutical composition, the sample is subjected to a temperature T for a period of time P. It is preferable that T is above room temperature. In specific embodiments of the method according to the invention, the temperature T is within the range of from 25° C. to 80° C., such as from 50° C. to 60° C.

The temperature T and the period of time P of the method according to the invention are jointly designed so as to provide a useful test answer in a desired period of time. In specific embodiments of the method according to the invention, the period of time P is less than two weeks, such as from 1 to 10 days. In a particular embodiment of the method according to the invention, the temperature T is approximately 56° C. and the period of time P is 10 days.

Following the preset period of time P, the concentration of the active ingredient in the pharmaceutical composition is determined using standard procedures, such as gas chromatography (GC), liquid chromatography (LC), high-performance liquid chromatography (HPLC), mass spectrometry (MS), or other suitable quantification techniques. The thus determined concentration is then compared with the initial concentration of the active ingredient in the pharmaceutical composition. Obviously, the initial concentration may be known beforehand or may be determined experimentally prior to the testing method. If the initial concentration is determined experimentally, it is preferable that the same method is used for determining the initial concentration and the resulting concentration following incubation in the presence of the material to be tested.

From this comparison, the stability provided by the material with respect to the active ingredient can be determined. It is thus possible to establish significant differences of the absorption/adsorption of one or more active ingredients between different candidate materials that would otherwise be considered to be equivalent in all respects. This method allows for a rapid and reliable screening of candidate materials for use in the containers according to the invention. Using the method according to the invention, suitable materials have been identified.

Hence, there is provided an inventive pharmaceutical composition storage container having a pharmaceutical composition. The pharmaceutical composition comprises one or more active ingredients in a therapeutically effective concentration and optionally a pharmaceutically acceptable excipient, dissolved and/or dispersed in an aqueous medium. The container is, at least partially, constructed of a pharmaceutically acceptable material comprising one or more polyolefins. Moreover, the material exhibits less than 20% sorption of the active ingredient(s) in a test, wherein a sample of the material, having a surface area 5, is immersed in a volume V of the pharmaceutical composition, the surface area to volume ratio S/V being about 20 cm⁻¹. The test may be performed according to the method described above. In specific embodiments, the test is performed at a temperature of 56° C. for 1, 3, 5 or 10 days.

All surfaces of the container that are exposed to the composition are constructed of the selected material. In particular, said container may consist of said material.

The material comprises ethylene or propylene monomers, or both. Without being limited thereto, the polyolefins may be selected from the group consisting of low-density polyethylene (LDPE), high-density polyethylene (HDPE), polypropylene (PP), and blends thereof. Optionally, the polyolefins are homopolymers. Specific polyolefins that are useful as material in the container according to the invention are DuPont™ 20 LDPE, Chevron 5502 HDPE, Atofina 3020 PP, and others, such as polypropylene homopolymers, low ethylene content (<8%) polypropylenes, and polymers (HDPE, PP) with low content of additives (<5%) and with low flexural modulus (<200 kpsi).

The active ingredient in any of the aspects or embodiments of the invention is selected from prostaglandins and analogues and derivatives thereof.

Analogues of the natural prostaglandins include, but are not limited to, compounds resulting from modifications of the omega chain (e.g. 18,19,20-trinor-17-phenyl, 17,18,19,20-tetranor-16-phenoxy), which enhance selectivity of action and reduce ocular side-effects.

The initial concentration of the selected active ingredient in said composition may vary depending on the therapeutically effective concentration. For example, the concentration of the selected active ingredient may be in the range of from 0.001% to 5% (w/v). In certain preferred embodiments, the active ingredient is latanoprost. Therapeutically effective concentrations of latanoprost may be in the range of 1-1000 μg/ml, preferably 10-100 μg/ml.

As discussed previously, certain parameters of the method may vary depending on e.g. the active ingredient, the container material, the desired stability/degree of sorption, the selected surface area, volume, incubation temperature, and incubation time.

Again, certain parameters of the selected material and its test values may vary depending on e.g. the active ingredient, the desired stability/degree of sorption, the selected surface area, volume, incubation temperature, and incubation time.

Without being limited thereto, the present invention will in the following be further illustrated by way of examples.

EXAMPLES Example 1

Beads were prepared from a number of candidate materials (see Table 1). The surface area S of the beads were 40 cm². The beads were immersed in a glass vial with teflonlined polypropylene screw caps containing 2 mL solution of 50 μg/mL. The ratio S/V between the exposed surface area S of the beads and the volume V of the solution was 20 cm⁻¹.

The glass vials were tightly capped and incubated at 56° C. for up to 10 days. Samples (50 μl) were withdrawn from the vials at 1, 3, 7 and 10 days, and the concentration of the active ingredient was determined using HPLC. Results are given in Table 1 below. TABLE 1 Latanoprost remaining in solution after storage at 56° C. % Latanoprost % Latanoprost % Latanoprost remaining after remaining after remaining after ID Resin 23 hrs (Day 1) 56 hrs (Day 3) 235.5 hrs (Day 10) Control (No Beads) 100 100 100 ATOFINA A1 PP 3020 SM3 97.27 89.95 80.15 A2 PP 3230 homopolymer 98.12 94.07 88.67 A3 PP 6253 95.45 87.88 79.38 A4 PP 7231X 94.42 83.37 72.01 A5 PP 8473 91.55 83.02 72.33 A6 PP Z9450 83.41 72.41 55.46 HUNTSMAN H1 PP 23M2CS038 95.83 90.85 84.56 H2 PP 23M2CS260 98.79 91.41 86.76 OTHER X1 Equistar PP 8752HF 89.99 80.88 63.76 X2 Exxon Exact 3024 73.01 63.26 53.91 X3 Dupont ™ LDPE 20 92.14 90.22 88.98 X4 Dupont ™ LDPE 20-6064 84.36 72.52 59.69 X5 Chevron HDPE 98.6 96.59 85.51 5502BN X6 Pexane-Basell 82.19 74.02 54.91 PP C400F

Thus, we have determined that e.g. the materials Dupont™ LDPE 20, Chevron 5502 HDPE, Atofina 3020 PP, and homopolymers of PP and HDPE are capable of providing improved stability of packaged formulations of active ingredient and will constitute suitable package materials. A similar study has also indicated the need to stay away from LLDPE (linear low-density PE) as any component of the primary package as well as to avoid gamma-irradiated materials.

Example 2

The general procedure of Example 1 is followed, but instead of beads, the candidate materials are prepared in the form of discs (approximate surface area 19 cm² with 2 mL of solution so that S/V=10 cm⁻¹). The results of this study are given in Table 2 below. TABLE 2 Latanoprost Remaining in Solution After Incubation with Different Polymer Discs at 56° C. for up to 10 Days % of Latanoprost remaining ID Polymer Disc Material Day 1 Day 5 Day 9 MDH Marlex BM01A (PP) 85.54 79.76 77.88 BDH Eltex PP KL 167N8058 95.58 89.58 91.41

Example 3

The general procedure of Example 1 is followed for a number of materials, but the parameters in Table 3 are employed. TABLE 3 Experimental Parameters Surface Composition Area/volume Incubation Incubation Active ingredient area S volume V S/V temperature T time P latanoprost   40 cm²  2 mL  20 cm⁻¹ 56° C. 10 days 17-phenyl-   10 cm²  2 mL  5 cm⁻¹ 25° C. 14 days 18,19,20-trinor- PGF_(2a)-isopropyl ester unoprostone isopropyl  200 cm²  6 mL  33 cm⁻¹ 60° C.  5 days latanoprost  1200 cm²  20 mL  60 cm⁻¹ 37° C. 10 days travoprost 10000 cm² 100 mL 100 cm⁻¹ 75° C.  3 days

Example 4

Packages for compositions of various prostaglandins, including latanoprost, are prepared from the materials of Example 1 and 2. The packages are in the form of bottles suitable for ophthalmic use. The bottles are of various designs; the materials may form part of the package or may constitute the entire package. In certain bottles, the design is modified so as to include small areas of flexibility (thinner walls), which give more functional dropper bottles when HDPE or homopolymers of PP form the major constituent of material of construction.

Example 5

Medicinal products according to the invention are prepared by the following procedure. Bottle-type containers with an inner volume of approximately 5 mL are prepared by standard techniques from the materials Dupont™ LDPE 20, Chevron 5502 HDPE and Atofina 3020 PP respectively. The bottles are filled with 2.5 mL of XALATAN® (latanoprost 50 μg/ml). The bottles are suitable for ophthalmic use.

While the invention has been illustrated by reference to specific and preferred embodiments, those skilled in the art will recognize that variations and modifications may be made through routine experimentation and practice of the invention. Thus, the invention is intended not to be limited by the foregoing description, but to be defined by the appended claims and their equivalents. 

1. A container comprising, a) one or more polyolefins exhibiting less than 20% sorption of one or more active ingredients as determined by a suitably acceptable method; and b) a composition comprising said one or more active ingredients.
 2. The container according to claim 1, wherein the suitably acceptable method comprises the steps of: a) providing a sample of said container having a surface area of S; b) immersing said sample in a volume V of said composition, such that the surface area to volume ratio S/V is in the range of from about 1 to about 100 cm⁻¹; and c) subjecting said sample immersed in said composition to a temperature T that is above room temperature for a period of time P that is less than two weeks.
 3. The container according to claim 2, wherein said P is 10 days.
 4. The container according to claim 2, wherein said T is 56° C.
 5. The container according to claim 1, wherein said one or more polyolefins comprise either ethylene monomers, propylene monomers, or both.
 6. The container according to claim 5, wherein said one or more polyolefins are selected from the group consisting of low-density polyethylene (LDPE), high-density polyethylene (HDPE), polypropylene (PP), and blends thereof.
 7. The container according to claim 6, wherein said one or more polyolefins are selected from the group consisting of homopolymers of low-density polyethylene (LDPE), homopolymers of high-density polyethylene (HDPE), and homopolymers of polypropylene(PP).
 8. The container according to claim 5, wherein said one or more polyolefins are selected from the group consisting of DuPont™ 20 LDPE, Chevron 5502 HDPE, Atofina 3020 PP, polypropylene homopolymers, low ethylene content (<8%) polypropylenes, and polymers (HDPE, PP) with low content of additives (<5%) and with low flexural modulus (<200 kpsi).
 9. The container according to claim 1, wherein said one or more polyolefins exhibit less than 10% sorption of one or more said active ingredient(s).
 10. The container according to claim 9, wherein said one or more polyolefins exhibit less than 5% sorption of said active ingredient(s).
 11. The container according to claim 1, wherein said composition is an ophthalmic composition.
 12. The container according to claim 11, wherein said ophthalmic composition is for treatment of glaucoma.
 13. The container according to claim 1, wherein said one or more active ingredient(s) is selected from the group consisting of prostaglandin, analogues, and derivatives thereof.
 14. The container according to claim 13, wherein said one or more active ingredient(s) comprises one or more physiologically acceptable derivatives of prostaglandin F (PGF), in which the omega chain has the formula:

the bond between C₁₃ and C₁₄ is optionally a single bond or double bond; D is a chain with 2-3 carbon atoms, optionally comprising at least one heteroatom selected from the group consisting of O, S, and N, and optionally substituted by one or more substituents selected from the group consisting of H, C₁-C₅ alkyl, halo, keto and hydroxy; R is a (i) phenyl group optionally substituted by one or more substituents selected from the group consisting of C₁-C₅ alkyl, C₁-C₄ alkoxy, trifluoromethyl, C₁-C₃ aliphatic acylamino, nitro, halo, and phenyl; or (ii) an aromatic heterocyclic group having 5-6 ring atoms, selected from the group consisting of thiozol, imidazole, pyrrolidine, thiophene and oxazole, optionally substituted by one or more substituents selected from the group consisting of C₁-C₅ alkyl, C₁-C₄ alkoxy, trifluoromethyl, C₁-C₃ aliphatic acylamino, nitro, halo, and phenyl; or (iii) C₃-C₇ cycloalkyl or C₃-C₇ cycloalkylene optionally substituted by C₁-C₅ alkyl.
 15. The container according to claim 14, wherein said one or more physiologically acceptable derivatives of PGF are selected from the group consisting of 17-phenyl-18,19,20-trinor derivatives, 13,14-dihydro-17-phenyl-18,19,20-trinor derivatives, 16-phenoxy-17,18,19,20-tetranor derivatives, and 16-phenyl-17,18,19,20-tetranor derivatives.
 16. The container according to claim 15, wherein said active ingredient is latanoprost.
 17. The container according to claim 13, wherein the concentration of said active ingredient in said composition is in the range of from 0.001% to 5% (w/v).
 18. A medicinal product comprising a container according to claim 1, wherein said container contains a pharmaceutical composition according to claim
 1. 19. A method of determining whether a package material will provide a desired stability of an active ingredient of a pharmaceutical composition, said pharmaceutical composition comprising said active ingredient in a therapeutically effective concentration and optionally a pharmaceutically acceptable excipient, dissolved and/or dispersed in an aqueous medium, comprising the steps of: (i) providing a sample having a surface area S of said package material; (ii) immersing said sample of step (i) in a volume V of said composition, such that the surface area to volume ratio S/V is in the range of from about 1 to about 100 cm⁻¹; (iii) subjecting said sample immersed in said composition of step (ii) to a temperature T that is above room temperature, for a period of time P that is less than two weeks; (iv) following said period of time P of step (iii), calculating the concentration of said active ingredient; and (v) calculating the stability provided by the sample by comparing the concentration determined in step (iv) with the initial concentration of said active ingredient.
 20. The method according to claim 19, wherein said one or more active ingredient(s) are selected from prostaglandins, analogues and derivatives thereof.
 21. The method according to claim 20, said active ingredient(s) being selected from the group consisting of physiologically acceptable derivatives of PGF, in which the omega chain has the formula:

the bond between C₁₃ and C₁₄ is optionally a single bond or double bond; D is a chain with 2-3 carbon atoms, optionally comprising at least one heteroatom selected from the group consisting of O, S, and N, and optionally substituted by one or more substituents selected from the group consisting of H, C₁-C₅ alkyl, halo, keto and hydroxy; R is a (i) phenyl group optionally substituted by one or more substituents selected from the group consisting of C₁-C₅ alkyl, C₁-C₄ alkoxy, trifluoromethyl, C₁-C₃ aliphatic acylamino, nitro, halo, and phenyl; or (ii) an aromatic heterocyclic group having 5-6 ring atoms, selected from the group consisting of thiozol, imidazole, pyrrolidine, thiophene and oxazole, optionally substituted by one or more substituents selected from the group consisting of C₁-C₅ alkyl, C₁-C₄ alkoxy, trifluoromethyl, C₁-C₃ aliphatic acylamino, nitro, halo, and phenyl; or (iii) C₃-C₇ cycloalkyl or C₃-C₇ cycloalkylene optionally substituted by C₁-C₅ alkyl.
 22. The method according to claim 21, wherein said physiologically acceptable derivatives of PGF are selected from the group consisting of 17-phenyl-18,19,20-trinor derivatives, 13,14-dihydro-17-phenyl-18,19,20-trinor derivatives, 16-phenoxy-17,18,19,20-tetranor derivatives, and 16-phenyl-17,18,19,20-tetranor derivatives.
 23. The method according to claim 22, wherein said one or more active ingredient is latanoprost.
 24. The method according to claim 20, wherein the initial concentration of said one or more active ingredient in said composition is in the range of from 0.001% to 5% (w/v).
 25. The method according to claim 19, wherein said surface area to volume ratio S/V is in the range of from about 10 to about 40 cm⁻¹.
 26. The method according to claim 25, wherein said surface area to volume ratio S/V is about 20 cm⁻¹.
 27. The method according to claim 19, wherein said temperature T is in the range of from 25° C. to 80° C.
 28. The method according to claim 27, wherein said temperature T is in the range of from 50° C. to 60° C.
 29. The method according to claim 28, wherein said period of time P is in the range of from 1 to 10 days.
 30. The method according to claim 29, wherein said material comprises one or more polyolefins.
 31. The method according to claim 30, wherein said one or more polyolefins comprise either ethylene monomers, propylene monomers, or both.
 32. The method according to claim 19, wherein said sample of said material is provided in the shape of discs and/or pellets and/or beads.
 33. A method of maintaining the concentration of an active ingredient of a pharmaceutical composition upon storage in a container, comprising the steps of: (i) providing said pharmaceutical composition, comprising said active ingredient in a therapeutically effective concentration and optionally a pharmaceutically acceptable excipient, dissolved and/or dispersed in an aqueous medium; (ii) providing said container, which is comprised, at least partially, of a pharmaceutically acceptable material comprising one or more polyolefins, said material exhibiting less than 20% sorption of said active ingredient as measured by immersing a sample of said material having a surface area S in a volume V of said composition, the surface area to volume ratio S/V being about 20 cm⁻¹, at a temperature of 56° C. for 10 days; and (iii) storing said pharmaceutical composition in said container.
 34. A method of manufacturing a storage container utilizing a pharmaceutically acceptable material comprising one or more active ingredients in a therapeutically effective concentration and optionally a pharmaceutically acceptable excipient, dissolved and/or dispersed in an aqueous medium, wherein said material (i) comprises one or more polyolefins; and (ii) exhibits less than 20% sorption of said active ingredient(s) as measured by immersing a sample of such material having a surface area S in a volume V of said composition, the surface area to volume ratio S/V being about 20 cm⁻¹, at a temperature of 56° C. for 10 days. 